Individualized Dose-Response to Statins Associated With Cardiovascular Disease Outcomes

Background Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using 3 distinct pharmacological properties: 1) E0 (baseline LDL-C), 2) ED50 (potency: median dose achieving 50% reduction in LDL-C); and 3) Emax (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown. Objectives The authors analyzed the relationship between ED50 and Emax with real-world cardiovascular disease outcomes. Methods We leveraged deidentified electronic health record data to identify individuals exposed to multiple doses of the 3 most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal health care. We derived ED50 and Emax to quantify the relationship with a composite primary end point of ASCVD events (ischemic heart disease, cerebrovascular disease, peripheral vascular disease, coronary artery revascularization procedure) and all-cause mortality. Results We estimated ED50 and Emax for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED50 and Emax are independently associated with the primary end point. Hazard ratios were 0.85 (P < 0.01), 0.83 (P < 0.01), and 0.87 (P = 0.10) for ED50 and 1.13 (P < 0.001), 1.06 (P < 0.001), and 1.15 (P = 0.009) for Emax in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively. Conclusions The class-wide association of ED50 and Emax with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.